Clinical Trials Register

Summary
EudraCT Number:	2014-004972-49
Sponsor's Protocol Code Number:	CLFG316X2202
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2016-02-23
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

France - ANSM

A.2

EudraCT number

2014-004972-49

A.3

Full title of the trial

A randomized, open label, controlled, multiple dose study
to evaluate the clinical efficacy, safety, tolerability,
pharmacokinetics and pharmacodynamics of LFG316 in
patients with transplant associated microangiopathy after
hematopoietic precursor cell transplantation

Étude randomisée, ouverte, contrôlée, à doses multiples, évaluant
l’efficacité clinique, la sécurité d’emploi, la tolérance, la
pharmacocinétique et la pharmacodynamie de LFG316 chez des
patients ayant une microangiopathie thrombotique liée à la greffe
après allogreffe de cellules souches hématopoïétiques

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

The study is to gather evidence of LFG316 efficacy in
treatment of transplant associated microangiopathy (TAM) after hematopoetic precursor cell transplantation.

Cette étude est destinée à recueillir des données préliminaires sur l’efficacité de LFG316 dans le traitement de la MAT après allogreffe de CSH.

A.3.2

Name or abbreviated title of the trial where available

CLFG316X2202

A.4.1

Sponsor's protocol code number

CLFG316X2202

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Novartis Pharma Services AG
B.1.3.4	Country	Switzerland
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Novartis Pharma Services AG
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Novartis Pharma S.A.S
B.5.2	Functional name of contact point	Information&Communication Médicales
B.5.3	Address:
B.5.3.1	Street Address	2 et 4 rue Lionel Terray
B.5.3.2	Town/ city	Rueil-Malmaison
B.5.3.3	Post code	92500
B.5.3.4	Country	France
B.5.4	Telephone number	+33 155476600
B.5.5	Fax number	+33 155476100
B.5.6	E-mail	icm.phfr@novartis.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.2	Product code	LFG316
D.3.4	Pharmaceutical form	Powder for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	NA
D.3.9.2	Current sponsor code	LFG316
D.3.9.4	EV Substance Code	SUB32390
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	100
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Transplant associated microangiopathy (TAM)

Microangiopathie thrombotique liée à la greffe (MAT)

E.1.1.1

Medical condition in easily understood language

Transplant associated microangiopathy

Microangiopathie thrombotique liée à la greffe

E.1.1.2

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.1
E.1.2	Level	LLT
E.1.2	Classification code	10050444
E.1.2	Term	Microangiopathy NOS
E.1.2	System Organ Class	100000004866

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

To assess the hematological response rate in
patients with TAM receiving LFG316
compared to standard of care (SoC)

Cette étude est principalement destinée à recueillir des données préliminaires sur l’efficacité de LFG316 dans le traitement de la MAT après allogreffe de CSH.

E.2.2

Secondary objectives of the trial

To assess the safety and tolerability of
LFG316 in patients with TAM
To describe the pharmacokinetics of total
LFG316
To evaluate non-relapse mortality in TAM
patients treated with LFG316 as compared to
patients on SoC
To assess complete response rate at 17 weeks
in TAM patients treated with LFG316
compared to patients receiving standard of
care

Evaluer la sécurité d’emploi et la tolérance de LFG316 chez les patients ayant une MAT;
Décrire les paramètres pharmacocinétiques (PK) de LFG316 total
Evaluer la mortalité sans rechute chez les patients ayant une MAT traités par LFG316 + traitement standard versus traitement standard;
Evaluer le taux de réponse complète à 17 semaines chez les patients ayant une MAT traités par LFG316 + traitement standard versus traitement standard

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.Written informed consent/assent before any study-specific screening procedures.
For pediatric patients, consent will be obtained from parent(s) or legal guardian(s) and the
signature of at least 1 parent or guardian will be required. Investigators will also obtain
assent of patients according to local, regional or national guidelines.
2. Male and female TAM patients ≥ 2 years old at the time of first dose administration.
Patients < 12 years old can only be included in the study after first IA has shown that it is
safe and well tolerated in patients ≥ 12 years old (Section 3.5).
3. The presence of TAM as per below diagnostic criteria at baseline (or screening if baseline visit is skipped). All the criteria have to be met for the patients included in the study:  Elevated lactate dehydrogenase (any elevation above normal range)
 Thrombocytopenia with platelet count < 50x10e9/L or greater than >50% decrease in
platelet count from the highest value achieved after transplant
 Anemia below lower limit of normal or anemia requiring transfusion support as per
center standard
 Schistocytes on peripheral blood smear (>2 per HPF) OR histologic evidence of
microangiopathy
 Absence of coagulopathy (no uncompensated disseminated intravascular coagulation, DIC) at screening
4. The presence of TAM high risk features at baseline (or screening if baseline visit is
skipped): Patients ≤ 16 years must have a Lansky score of ≤ 70 and patients > 16 must
have Karnofsky score ≤ 70% and/or proteinuria (> 30 mg/dL) measured in two urine spot analyses.
5. Hypertension, defined for adults by SBP ≥ 160 mmHg and DBP ≥ 100 mmHg at baseline
(or screening if baseline visit is skipped), and for pediatric patients by blood pressure
greater than the 95th percentile for age, sex, and height (see Table 16-1). Additionally,
patients who were started on antihypertensive medication after HSCT or who have received additional antihypertensive medication after HSCT will be eligible, even if they don’t have elevated blood pressure
6. Meningococcal vaccine(s) prior to LFG316 treatment if prior vaccination cannot be
confirmed. The choice of vaccine(s) should take into account the serotypes prevalent in
the geographic areas in which study patients will be enrolled.
7. Whenever possible, patients <18 years old should receive vaccination for the prevention
of S. pneumoniae and H. influenzae type b prior to LFG316 administration
8. Weight of at least 10kg.

1.Patient ayant donné son consentement écrit avant toute évaluation,
2.Patient féminin ou masculin âgé(e) d’au moins 2 ans au moment de la première administration du traitement. Les patients < 12 ans pourront être inclus une fois que l’analyse intermédiaire aura démontré la sécurité d’emploi et la tolérance du LFG316 chez les patients ≥ 12 ans,
3.Diagnostic de MAT à la visite de baseline (ou à la sélection si la visite de baseline n’a pas lieu) remplissant tous les critères suivants :
•Elévation des LDH (toute valeur au-dessus des normes),
•Thrombopénie < 50 x 109/l ou diminution > 50% par rapport à la plus haute valeur obtenue après la greffe,
•Anémie < LIN ou anémie nécessitant une transfusion selon les critères du centre,
•Schizocytes sur un frottis de sang périphérique (> 2 / HPF) ou signe histologique de microangiopathie,
•Absence de coagulopathie [pas de coagulation intravasculaire disséminée (CIVD) décompensée],
4.MAT à haut risque : indice de Karnofsky ≤ 70% ou indice de Lansky ≤ 70 (pour les patients ≤ 16 ans) et/ou protéinurie > 30 mg/dl sur 2 échantillons urinaires,
5.Hypertension définie chez les adultes par PAS ≥ 160 mmHg et PAD ≥ 100 mmHg et chez les enfants par une PA > 95ème percentile de l’âge, du sexe et de la taille (cf. annexe 2 du protocole). De plus les patients ayant démarré un traitement antihypertenseur ou ayant reçu un traitement antihypertenseur supplémentaire après l’allogreffe de CSH seront éligibles même si leur PA n’est pas élevée,
6.Vaccination contre le méningocoque à faire avant la première administration de LFG316 si une précédente vaccination ne peut être confirmée. Le choix du vaccin prendra en compte la prévalence des sérotypes dans la région d’inclusion,
7.Si possible les patients < 18 ans devront être vaccinés contre le pneumocoque et H. influenzae type b avant la première administration de LFG316,
8.Poids ≥ 10 kg.

E.4

Principal exclusion criteria

1.Use of other investigational drugs at the time of enrollment, or within 5 half-lives of
enrollment, or until the expected PD effect has returned to baseline, whichever is longer;
or even longer if required by local regulations.
2. History of hypersensitivity to study drug or to drugs of similar chemical classes.
3. Patients with steroid refractory graft versus host disease (SRGvHD) (progression
(=increase in overall grade) after 5 days on ≥1mg/kg methylprednisolone or equivalent OR no improvement (no decrease in overall grade) after 10 days on ≥ 1mg/kg
methylprednisolone or equivalent).
4. Patients with ALT > 5x ULN.
5. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a
female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (at screening or baseline).
6. Women of child-bearing potential, defined as all women physiologically capable of
becoming pregnant, unless they are using highly effective methods of contraception
during dosing and for 45 days after stopping study medication.
7. Positive HIV (ELISA and Western blot) test result (checked at screening).
8. A positive Hepatitis B surface antigen or Hepatitis C test result at screening.
9. Patients with any severe, progressive or uncontrolled acute or chronic medical condition (such as uncontrolled infectious disease or sepsis) or clinical laboratory abnormalities that in the investigator’s opinion would make the patient inappropriate for entry into this study (at screening or baseline).
10. Patients with proven TTP as per historical data (as defined by ADAMST13 activity test)
and if already available results of ADAMST13 test done at screening.
11. Patients previously treated with eculizumab for TAM.
12. Patents with known or suspected hereditary complement pathway deficiency

1.Utilisation d'autres médicaments à l’essai au moment du recrutement, dans les 5 demi-vies précédant le recrutement, ou temps que l’effet PD attendu n’est pas revenu à l’état basal, la plus longue des durées prévalant,
2.Antécédents d’hypersensibilité au traitement de l’étude ou à des médicaments de classe chimique similaire,
3.Réaction de GVH résistante aux corticoïdes [progression (augmentation du grade après 5 jours à ≥ 1mg/kg de méthylprednisolone ou équivalent) ou pas d’amélioration (pas de diminution du grade après 10 jours à ≥ 1mg/kg de méthylprednisolone ou équivalent)],
4.ALAT > 5 x LSN (limite supérieure de la norme)
5.Femme enceinte ou allaitant, la grossesse étant définie comme la période entre la conception et l’accouchement et devant être confirmée par un dosage positif des taux sanguins d’HCG,
6.Femme en âge de procréer, à savoir toute femme physiologiquement apte à être enceinte, sauf si elle utilise des moyens de contraception efficaces pendant toute l'administration du traitement de l'étude et pendant 45 jours après la dernière administration. Les moyens de contraception efficaces sont décrits dans le protocole,
7.VIH + (ELISA et Western blot réalisés à la sélection),
8.Résultat positif à la sélection du test Hépatite B (AgHBs) ou hépatite C,
9.Toute maladie chronique ou aigue sévère, progressive ou non contrôlée (comme une maladie infectieuse non contrôlée ou une septicémie) ou toute anomalie biologique qui contre-indique l’inclusion du patient dans l’étude (à la sélection ou à la baseline) selon le jugement de l’investigateur,
10.Antécédent de PTT confirmé (test d’activité ADAMTS13) si le résultat du test est disponible à la sélection,
11.Traitement antérieur par éculizumab pour une MAT,
12.Déficit de la voie du complément héréditaire connu ou suspecté.

E.5 End points

E.5.1

Primary end point(s)

Hematological response at 17 weeks where a
patient is considered to be a responder if both
of the following criteria are met:
1. Schistocytes <2/microscopic high power field
(HPF).
2.Transfusion independent (no need for
TAM-related transfusions (platelets and
erythrocytes))

Réponse hématologique à 17 semaines ; un patient étant considéré répondeur s’il présente les 2 critères suivants :
1.Schizocytes < 2 / champ en microscopie électronique
2.Plus de besoin de transfusion lié à la MAT (plaquettes + érythrocytes)

E.5.1.1

Timepoint(s) of evaluation of this end point

17 weeks

17 semaines

E.5.2

Secondary end point(s)

All safety parameters including: blood
chemistry, hematology, proteinuria, body
height/weight, urinalysis, ECG evaluation,
Adverse events, body temperature, blood
pressure, physical examination, pulse rate,
Lansky/Karnofsky score
Serum total LFG316 concentrations
Non-relapse mortality is any death not
considered to be related to a relapse of underlying disease. Complete response is defined as hematological response and no proteinuria as determined by
proteinuria <30mg/dL and eGFR doubled or not less than 0.85 x lower limit of normal underlying disease Complete response is defined as hematological response and no proteinuria as determined by proteinuria <30mg/dL and eGFR doubled or not less than 0.85 x lower limit of normal

Tous les paramètres de tolérance : biochimie du sang, hématologie, protéinurie, taille/poids, analyses urinaires, ECG, évènements indésirables (EI), température corporelle, pression artérielle, examen clinique, pouls, indice de Karnofsky ou Lansky (patients ≤ 16 ans)
Concentrations sériques de LFG316 total
La mortalité sans rechute correspond à tous les décès considérés non liés à une rechute de la maladie initiale
La réponse complète est définie comme une réponse hématologique (cf. critère principal ci-dessus) en l’absence de protéinurie :
•Protéinurie < 30 mg/dl
et
•Débit de filtration glomérulaire estimé (DFGe) doublé ou ≥ 0,85 x limite inférieure de la norme (LIN)

E.5.2.1

Timepoint(s) of evaluation of this end point

45weeks

45 semaines

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Tolerability

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Standard of care

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

France

Germany

United States

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

DVDP

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1

Number of subjects for this age range:

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

Yes

F.1.1.5.1

Number of subjects for this age range:

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

For pediatric patients, consent will be obtained from parent(s) or legal guardian(s) and the
signature of at least 1 parent or guardian will be required.

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

At a minimum, subjects will be contacted for safety evaluations during the 30 days following the Study Completion visit, including a final post-study safety contact at the 30-day point.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2015-12-18

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-10-08

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2017-06-30

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IMP with orphan designation in the indication
Orphan Designation Number:
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